Factitious disorders in Germany-a detailed insight.

Factitious disorders (FDs) are well known to a majority of physicians; however, the corresponding ICD-10 diagnosis F68.1 remains severely under assigned and often misdiagnosed. Based on a previously conducted nationwide survey in Germany, we extended the analyzed variables to further understand FD characteristics.The assignments regarding the following variables in the German diagnosis-related group statistics were analyzed: residence of the patient and location of the diagnosing institution, primary referral to the diagnosing institution, reason for admission and discharge, specialty department, total length of stay, length of stay in the longest treating department, surgery performed, case mix revenue, regional type of the treating institution, and patients' region of origin.A very distinct difference was observed in the assignment rates based on the homeland of the diagnosed patient and diagnosing institution. The assignment rate showed no significant difference across German regions. Based on our findings, a patient with FD in Germany might exhibit the following "typical" traits: A woman in her late thirties from a rural area is referred by a physician or another hospital wherein she was previously treated for more than a day to an institution for fully inpatient hospital treatment wherein she completes her treatment regularly. Dermatology, neurology, emergency, and internal medicine departments tend to be confronted with patients with FDs more often than other departments; however, surgery is performed in every fifth case. Patients are primarily treated in only one department for ~ 25 days. The case mix revenue will most probably not exceed €5000.

Fox sign in a case of terminal stage pancreatic cancer and suggestions for diagnosis.

Skin signs in acute pancreatitis are well-known and frequently discussed manifestations accompanied by unfavorable prognoses although they may rarely appear in clinical and forensic medicine. In 2018, the district attorney's office ordered a forensic autopsy for a 74-year-old man with terminal stage pancreatic cancer. The autopsy was ordered based on accusations of the deceased's widow regarding alleged medical malpractice and poor hospital care. The widow filed a grievance about multiple unsuccessful attempts to draw blood from her husband in addition to a diaper dermatitis at the right groin. An autopsy and additional histological examinations were performed. After considering all findings, the diaper dermatitis was eventually assumed to be a Fox sign caused by acute pancreatitis, and the allegations of medical malpractice were refuted. This case led us to identify another case with suspected cutaneous manifestations in pancreatic disease. We performed immunohistochemical staining on those two cases and six control cases to examine whether there was detectable presence of pancreatic lipase and trypsin in the skin discolorations and whether it could be used as a feasible method to verify skin signs associated with pancreatitis. Based on our findings, a minor disseminated lipase and trypsin staining should be considered regular and is therefore not conclusive of a skin sign associated with pancreatitis. Moreover, trypsin does not seem to be as suitable as lipase for this suggested immunohistochemical method. Nevertheless, this method might be a useful addition for determining the origin of skin discoloration and verifying skin signs associated with pancreatitis.

Detectability of various cannabinoids in plasma samples of cannabis users: Indicators of recent cannabis use?

To assess the informative value of determining (minor) cannabinoids in plasma of cannabis users, detection rates of 14 cannabinoids (next to Δ9 -THC and THC-COOH) were determined. 11-OH-THC, THCA, CBC, CBN, and CBD were the most frequent detectable cannabinoids. The dependency of cannabinoid detectability on the plasma Δ9 -THC concentration was examined.

Palmitic acid ester of tetrahydrocannabinol (THC) and palmitic acid diester of 11-hydroxy-THC - Unsuccessful search for additional THC metabolites in human body fluids and tissues.

Fatty acid conjugates of hydroxy-metabolites of tetrahydrocannabinol (THC) or cannabinol have already been reported as metabolites in rats. In the herein presented investigation, palmitic acid esters of THC and its primary metabolite 11-hydroxy-delta9-tetrahydrocannabinol (11-OH-THC) were synthesized using esterification with palmitic acid chloride. Structural elucidation of the products was conducted using nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography coupled to quadrupole time of flight mass spectrometry (LC-QToF-MS). For the confirmation of a previous cannabis use, body fluids (femoral blood, heart blood, urine, bile) of 27 death cases (all with known cannabis use), including adipose tissue homogenates of six of these cases as well as eleven plasma samples (probably all with regular cannabis use, confirmed by a high 11-nor-9-carboxy-delta9-tetrahydrocannabinol (THC-COOH) concentration (except one sample, >200ng/mL), were tested for THC and its main metabolites 11-OH-THC and THC-COOH using gas chromatography coupled to mass spectrometry (GC-MS). These samples as well as further tissue homogenates of autopsy cases (liver, kidney, brain) were additionally tested for the presence of THC palmitic acid ester or 11-OH-THC palmitic acid diester by means of a liquid chromatographic triple quadrupole mass spectrometric (LC-QQQ-MS) method, in order to evaluate a possible presence of these conjugates in humans. In none of the analyzed samples (in total 196 specimens; plasma (N=11), femoral blood (N=23), heart blood (N=25), urine (N=23), bile (N=27), liver (N=27), kidney (N=27), brain (N=27), adipose tissue (N=6)), palmitic acid esters of THC or 11-OH-THC could be proven. Even if the existence of these esters in human samples cannot be ruled out definitely, suitability as cannabis consumption markers does not seem likely based on our findings.

Confirmation of recent heroin abuse: Accepting the challenge.

Confirmation or exclusion of recent heroin consumption is still one of the major challenges for forensic and clinical toxicologists. A great variety of biomarkers is available for heroin abuse confirmation, including various opium alkaloids (eg, morphine, codeine), street heroin impurities (eg, 6-acetylcodeine [6-AC], noscapine, papaverine) as well as associated metabolites (eg, 6-monoacetylmorphine [6-MAM], morphine glucuronides). However, the presence of most of these biomarkers cannot solely be attributed to a previous heroin administration but can, among other things, also be due to consumption of poppy seed products ('poppy seed defense'), opium preparations or specific medications, respectively. A reliable allocation is of great importance in different contexts, for instance in the case of DUID (driving under the influence of drugs) investigations, in driving licence re-granting processes, in workplace drug testing (WDT), as well as in post-mortem identification of illicit opiate use. Additionally, differentiation between illicit street heroin abuse and pharmaceutical heroin administration is also important, especially within the frame of heroin-assisted treatments. Therefore, analysis of multiple biomarkers is recommended when illicit opiate consumption is assumed to obtain the most reliable results possible. Beyond that, interpretation of positive opiate test results requires a profound insight into the great variety of biomarkers available and their validity regarding the alleged consumption. This paper aims to provide an overview of the wide variety of heroin abuse biomarkers described in the literature and to review them regarding their utility and reliability in daily routine analysis.

Expression of Hsp27 and Hsp70 and vacuolization in the pituitary glands in cases of fatal hypothermia.

Hypothermia causes systemic cellular stress. The pituitary gland is an endocrine gland and plays an important role in thermoregulation. When the core body temperature drops, the pituitary gland is activated by stimulation of hypothalamic hormones. In this study, we investigated morphological alterations of the pituitary gland in cases of fatal hypothermia. Several morphological alterations of the anterior lobe of the pituitary gland, such as hemorrhage, vacuolization, and hyperemia, have been previously described in fatal hypothermia. However, the diagnostic value of these findings is controversial. We compared 11 cases of fatal hypothermia with 10 cases lacking antemortem hypothermic influences. In the presence of thermal cellular stress, the expression of heat shock proteins increases to protect cellular structures. Therefore, we immunohistochemically analyzed Hsp27 and Hsp70. Hsp27 expression was detected in 27.3% of the cases of fatal hypothermia and in 10.0% of the control cases, whereas Hsp70 expression was not detected in any case. Additionally, Sudan staining was performed to quantify fatty degeneration. A positive reaction was found in 45.5% of the study group and in 10.0% of the control group. This indicates that fatty degeneration might be a valuable marker when other macroscopic signs of hypothermia are absent.

Fatal bleeding from an aortocoronary bypass.

Coronary bypass grafting is a routine procedure in heart surgery, which can now also be performed using a minimally invasive technique on the beating heart. In the presented case, a 55-year-old man died two days after bypass surgery. His condition had deteriorated post-operatively over 2 days until he finally died from multi-organ failure and cardiogenic shock. Autopsy revealed a fatal haemorrhage into the chest cavities from a small tear in the bypass and acute myocardial infarction. The haemorrhage had not been noticed in the hospital. Postoperative haemorrhage is a common complication after this type of surgery, which occurs in about 1-2 % of cases.

[Rare causes of iatrogenic pericardial tamponade - 2 case reports].

Two rare causes of iatrogenic pericardial effusions are presented. In the first case, a 61-year-old woman who had undergone laparoscopic surgery for a diaphragmatic hernia was resuscitated without success the next day. As cause of death circulatory failure as a result of post-operative pulmonary embolism was reported. Autopsy results showed that the pericardium and the heart had been sewn to the diaphragm. The suture was torn from the tissue, which caused a hemorrhage into the pericardium and the chest cavity, so that death was diagnosed to be due to cardiac tamponade and hemothorax after an iatrogenic heart injury. In the second case, a 62-year-old man who had developed a massive incisional hernia after treatment of an abdominal gunshot wound underwent open herniotomy with mesh repair. Postoperatively, the man complained about increasing pain and shortness of breath. He was transferred to another hospital for further assessment, where a cardiac tamponade was diagnosed. Autopsy results showed that three of the plastic staples used to fix the mesh had perforated the diaphragm and the pericardium thus injuring the adjacent right ventricle with subsequent perforation and development of a hemopericardium.

Microscopic examination of pituitary glands in cases of fatal accidental hypothermia.

In cases of death caused by hypothermia, histological analysis can be used to determine the cause of death. Certain histological alterations of the pituitary glands in hypothermia have been reported in the literature, including haemorrhage, hyperaemia and cellular vacuolization of cells in the anterior lobe. In the present study, the validity of these morphological alterations as markers for fatal accidental hypothermia was investigated in autopsy material. A total of 34 pituitary glands in cases of verified fatal accidental hypothermia were examined histologically (haematoxylin and eosin, ferric, azan) and immunohistochemically (LCA, ACTH, C5b-9). The findings were compared with 61 cases in a control group. Hyperaemia was found in 50.0% of the study group cases and 59.0% of the control group cases. Cellular vacuolization was observed in one case (2.9%) in the study group and one case (1.6%) in the control group. Acute or recent haemorrhage in the glandular tissue was never detected. In our study, the histopathological characteristics described in the literature as pathognomonic for hypothermia could not be confirmed. Furthermore, histological differences in the pituitary glands between fatal hypothermia cases and control group cases were not observed.

Forensic aspects of starvation.

Fatal starvation is a rare cause of death in industrialized countries. However, it may have major medicolegal importance if death results from the deliberate withholding of food, especially from infants. In such cases, the task of the forensic pathologist and the medical examiner, respectively, is to clarify the cause of death and give an expert opinion on the degree and duration of starvation. Several classification systems have been developed to estimate protein-energy malnutrition in developing countries. Simpler classifications, such as the Gomez classification, use the weight expected for the respective age group as the standard. However, smaller infants will be lighter, and therefore the classification may not be accurate in this case. Following the Waterlow classification, the extent of stunted growth (referring to growth retardation in cases of chronic malnutrition) is calculated using the ratio of the measured body height to that expected for the age. Using such classification systems, grading of stunting and wasting can be achieved and may greatly help in the assessment of a given child's nutritional status in legal cases. The application of the Waterlow classification to the authors' case material and previously published cases in the literature is herein demonstrated. The Waterlow classification is not only of importance for grading the final stage of fatal starvation, but also for the chronological development of the nutritional status if anthropometrical data have been repeatedly recorded from the affected individual in vivo.

[Fatal explosion injuries from blasting a cigarette machine]. / Tödliche Explosionsverletzungen bei Sprengung eines Zigarettenautomaten.

In the last few years, a growing number of cases have been reported in Germany in which vending machines have been blasted by criminals to get at the money. Thus, it was only a question of time for the first fatalities to occur as a consequence of such careless explosions. We report on the death of a 16-year-old boy who died after triggering an explosion by spraying a deodorant into the coin slot of a cigarette machine. Death was caused by severe craniocerebral trauma due to tertiary blast-related injuries when the front plate of the machine hit the victim's cerebral and facial skull.

Quantification of leucocytes, T-lymphocytes and macrophages in autoptical endomyocardial tissue from 56 normal human hearts during the first year of life.

This study evaluated the normal number of inflammatory cells in the heart in the first year of life using two methods to compare their ability to quantitate physiological myocardial infiltration. Eight endomyocardial samples from both ventricles were obtained at autopsy from 56 structurally normal hearts during the first year of life. In each sample the numbers of leucocytes, T-lymphocytes and macrophages were counted once in 20 randomly chosen high-power fields (400×) as well as in a 10mm(2) area of randomly chosen myocardial tissue (100×) by two independent investigators. Compared to the literature a greater representative proportion of myocardial tissue was analyzed. The results of the enumeration in mm(2) were converted into high-power-fields to compare both methods. The mean numbers and standard deviations for leucocytes, T-lymphocytes and macrophages were calculated. Both counting methods showed similar results with low inflammatory cell counts per single heart and staining. A greater understanding of the physiological myocardial infiltration by leucocytes, T-lymphocytes and macrophages is important for postmortem forensic cases, and for the interpretation of endomyocardial biopsies in infants.

[Immunohistochemical investigations on pulmonary tissue in cases of sudden infant death syndrome (SIDS)]. / Immunhistochemische Untersuchungen an Lungengewebe in Fällen des Plötzlichen Säuglingstodes (SIDS).

Numerous theories on the pathomechanism of SIDS favor a multifactorial genesis whereby infections of the upper respiratory tract and the pulmonary tissue have a trigger function. The aim of the presented study was to prove the presence of inflammatory responses in pulmonary tissue in SIDS cases because various studies revealed contradictory results about the evidence of inflammatory pulmonary responses in SIDS cases. For this purpose, 10 cases with defined causes of death were examined in comparison to 75 cases of sudden infant death syndrome (SIDS) with regard to CD45RO, CD68 and LCA positive cells in pulmonary tissue. Furthermore, the cell adhesion molecules E-selectin, P-selectin and VCAM were investigated. In the study group, the immunohistochemical imaging of CD45RO and LCA positive cells showed mostly negative results. There were no significant differences between study and control group as to the number of cells expressing CD45R0, CD68 and LCA. The same was true for the adhesion molecules E-selectin, P-selectin and VCAM.

Histological and immunohistochemical investigations on infantile pancreas in cases of sudden infant death syndrome (SIDS).

The sudden infant death syndrome (SIDS) is defined as unexpected death of a previously healthy infant with no cause of death being established. Comprehensive histological and immunohistochemical investigations are required subsequent to autopsy. In 18 cases of sudden infant death, histological (H&E, PAS and iron stain) and immunohistochemical investigations (CD68, CD45RO and LCA) were performed regarding a possible role of pancreatitis in SIDS and histomorphological alterations of the pancreatic islets, respectively. In all the investigated cases, no inflammatory changes of the infantile pancreatic tissue and no other significant histomorphological alterations of the pancreatic islets were found.

Immunohistochemical diagnosis of myocarditis on (infantile) autopsy material: Does it improve the diagnosis?

The standard for the histopathologic diagnosis of myocarditis has been the Dallas criteria. Recently, immunohistochemical studies that include the specification and quantification of interstitial inflammatory cells have been proposed as the diagnostic approach for myocarditis. Cut-off limits regarding inflammatory cell numbers for the positive diagnosis of myocarditis have been recommended. However, it is unclear whether these can be applied to postmortem tissues or to infants, as they were established from endomyocardial biopsies and for adults. Nevertheless, cut-off limits for the postmortem diagnosis of myocarditis in the first year of life have been proposed. Studies using these cut-off limits identified myocarditis in a high percentage of presumed sudden infant death syndrome (SIDS) cases. These results were re-evaluated by the present study, which examined heart specimens from infants less than 1 year of age. The study had a test group of 92 SIDS cases and a control group of 15. Myocardial tissue was examined from eight standardized locations, stained with hematoxylin-eosin and for three different immunohistochemical reagents (LCA for leukocytes, CD68 for macrophages, CD45-RO for T-lymphocytes). Histopathological assessment of the number of inflammatory cells was carried out on an aggregate of 80 mm(2) of myocardial tissue per case. Myocarditis, based on the Dallas criteria, was histologically diagnosed in only two cases. Immunohistochemical quantification revealed elevated cell counts in the SIDS group for LCA and CD45-RO. However, those differences were neither statistically significant nor clinically relevant as the mean cell counts per mm(2) were low. The density of inflammatory cells differed considerably from section to section and even within single sections. Therefore the commonly used arithmetic mean value was not diagnostically relevant, suggesting cut-off values based on the arithmetic mean value as recommended in the literature, cannot be regarded as valid. At least in infants, the diagnosis of myocarditis from autopsy tissues still requires application of the Dallas criteria. Immunohistochemical methods cannot replace the conventional diagnosis of myocarditis.

Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations.

Heteroplasmy in human mtDNA may play a role in cancer, other diseases, and aging, but patterns of heteroplasmy variation across different tissues have not been thoroughly investigated. Here, we analyzed complete mtDNA genome sequences at ∼3,500× average coverage from each of 12 tissues obtained at autopsy from each of 152 individuals. We identified 4,577 heteroplasmies (with an alternative allele frequency of at least 0.5%) at 393 positions across the mtDNA genome. Surprisingly, different nucleotide positions (nps) exhibit high frequencies of heteroplasmy in different tissues, and, moreover, heteroplasmy is strongly dependent on the specific consensus allele at an np. All of these tissue-related and allele-related heteroplasmies show a significant age-related accumulation, suggesting positive selection for specific alleles at specific positions in specific tissues. We also find a highly significant excess of liver-specific heteroplasmies involving nonsynonymous changes, most of which are predicted to have an impact on protein function. This apparent positive selection for reduced mitochondrial function in the liver may reflect selection to decrease damaging byproducts of liver mitochondrial metabolism (i.e., "survival of the slowest"). Overall, our results provide compelling evidence for positive selection acting on some somatic mtDNA mutations.

Staurosporine and extracellular matrix proteins mediate the conversion of small cell lung carcinoma cells into a neuron-like phenotype.

Small cell lung carcinomas (SCLCs) represent highly aggressive tumors with an overall five-year survival rate in the range of 5 to 10%. Here, we show that four out of five SCLC cell lines reversibly develop a neuron-like phenotype on extracellular matrix constituents such as fibronectin, laminin or thrombospondin upon staurosporine treatment in an RGD/integrin-mediated manner. Neurite-like processes extend rapidly with an average speed of 10 µm per hour. Depending on the cell line, staurosporine treatment affects either cell cycle arrest in G2/M phase or induction of polyploidy. Neuron-like conversion, although not accompanied by alterations in the expression pattern of a panel of neuroendocrine genes, leads to changes in protein expression as determined by two-dimensional gel electrophoresis. It is likely that SCLC cells already harbour the complete molecular repertoire to convert into a neuron-like phenotype. More extensive studies are needed to evaluate whether the conversion potential of SCLC cells is suitable for therapeutic interventions.

Identification of gunshots to the head by detection of RNA in backspatter primarily expressed in brain tissue.

Traces of backspatter recovered from the inside of the barrel of a gun that was used to deliver suicidal or homicidal contact shots may be a source of valuable forensic evidence and first systematic investigations of the persistence of victim DNA from inside firearms have been presented. The aim of the present study was to include victim RNA in such analyses to determine the origin of tissues in addition and parallel to standard DNA profiling for forensic identification purposes. In a first step, suitable mRNA (C1orf61) and micro-RNAs (miR-124a and miR-124*) that are primarily expressed in brain tissue were selected from potential candidates and confirmed using quantitative PCR (qPCR). Secondly, a co-extraction procedure for RNA and DNA was established and brain differentiability of the selected RNAs was demonstrated via qPCR using samples from experimental shots at ballistic models. In a third step, this procedure was successfully applied to analyse samples from real casework comprising eight cases of suicidal contact shots. In this pilot study, we are first to report the possibility of co-extracting mRNA, miRNA and DNA from ballistic trace samples collected from the inside of firearms and we demonstrate that RNA and DNA based analyses can be performed in parallel to produce informative and highly complementary evidence.

Lethal neuroleptic malignant syndrome due to amisulpride.

A 42-year old-man was found lying in his bed having seizures. Later he became unconscious and hypotonic developing mydriasis as well as rigidity. The body core temperature (rectal temperature) was above 42 °C. Blood pH was decreased during treatment, and his general condition deteriorated. The patient developed gasping respiration, ventricular fibrillation, and died. During autopsy and histological investigation cerebral and pulmonary edema were noted together with general congestion of the internal organs. Further observations included contraction bands of myocytes, a contracted spleen, fibrosis of the liver, and gall stones. Toxicological analyses of peripheral blood revealed the following results: amisulpride 4.65 mg/l, biperiden 0.12 mg/l, imipramine 0.33 mg/l, and desipramine 0.68 mg/l. An amisulpride-induced neuroleptic malignant syndrome was therefore diagnosed as the patho-physiological mechanism leading to death.